Aberrant splicing in B-cell acute lymphoblastic leukemia
Aberrant splicing in B-cell acute lymphoblastic leukemia
ABSTRACT Aberrant splicing is a hallmark of leukemias with mutations in splicing factor (SF)-encoding genes. Here we investigated its prevalence in pediatric B-cell acute lymphoblastic leukemias (B-ALL), where SFs are not mutated. By comparing them to normal pro-B cells, we found thousands of aberrant local splice variations (LSVs) per sample, with 279 LSVs in 241 genes present in every comparison. These genes were enriched in RNA processing pathways and encoded ~100 SFs, e.g. hnRNPA1. hnRNPA1 3’UTR was pervasively misspliced, yielding the transcript subject to nonsense-mediated decay. Thus, we knocked it down in B-lymphoblastoid cells, identified 213 hnRNPA1-dependent splicing events, and defined the hnRNPA1 splicing signature in pediatric leukemias. One of its elements was DICER1, a known tumor suppressor gene; its LSVs were consistent with reduced translation of DICER1 mRNA. Additionally, we searched for LSVs in other leukemia and lymphoma drivers and discovered 81 LSVs in 41 genes. 77 LSVs were confirmed using two large independent B-ALL RNA-seq datasets. In fact, the twenty most common B-ALL drivers showed higher prevalence of aberrant splicing than of somatic mutations. Thus, post-transcriptional deregulation of SF can drive widespread changes in B-ALL splicing and likely contribute to disease pathogenesis.
Naqvi Ammar S.、Yang Scarlett Y.、Gillespie Elisabeth、Pillai Vinodh、Carroll Martin、Taylor Deanne、Lynch Kristen W.、Thomas-Tikhonenko Andrei、Bagashev Asen、Black Kathryn L.、Gazzara Matthew R.、Barash Yoseph、Hayer Katharina E.、Tasian Sarah K.
Department of Pathology||Department of Biomedical & Health InformaticsDepartment of Pathology||Department of Immunology Graduate Group, School of Engineering, University of PennsylvaniaDepartment of PathologyDepartment of PathologyDepartment of Medicine, School of Engineering, University of PennsylvaniaDepartment of Biomedical & Health Informatics||Department of PediatricsDepartment of Biochemistry & Biophysics, School of Engineering, University of Pennsylvania||Department of Immunology Graduate Group, School of Engineering, University of PennsylvaniaDepartment of Pathology||Department of Pediatrics||Department of Pathology & Laboratory Medicine, Perelman School of Medicine, School of Engineering, University of Pennsylvania||Department of Immunology Graduate Group, School of Engineering, University of PennsylvaniaDepartment of PathologyDepartment of PathologyDepartment of Biochemistry & Biophysics, School of Engineering, University of Pennsylvania||Department of Genetics, School of Engineering, University of PennsylvaniaDepartment of Genetics, School of Engineering, University of Pennsylvania||Department of Computer and Information Science, School of Engineering, University of PennsylvaniaDepartment of Pathology||Department of Biomedical & Health InformaticsDepartment of Pediatrics
基础医学分子生物学肿瘤学
Naqvi Ammar S.,Yang Scarlett Y.,Gillespie Elisabeth,Pillai Vinodh,Carroll Martin,Taylor Deanne,Lynch Kristen W.,Thomas-Tikhonenko Andrei,Bagashev Asen,Black Kathryn L.,Gazzara Matthew R.,Barash Yoseph,Hayer Katharina E.,Tasian Sarah K..Aberrant splicing in B-cell acute lymphoblastic leukemia[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/225136.点此复制
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